Adenosine receptor agonists: synthesis and biological evaluation of the diastereoisomers of 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)NECA.
Among the recently reported 2-(ar)alkynyl derivatives of 5'-N-ethylcarboxamidoadenosine (NECA), the (R,S)-2-(3-hydroxy-3-phenyl-1-propyn-1-yl)NECA [(R,S)-PHPNECA or SCH 59761] was found to be a very potent agonist at A1 and A2A receptor subtypes, with a Ki of 2.5 nM and 0.9 nM, respectively. Furthermore, this compound showed an inhibitory activity on platelet aggregation 16-fold higher than NECA, being the most potent anti-aggregatory nucleoside reported so far. Since this compound bears a chiral carbon in the side chain, the diastereoisomer separation was undertaken both by chiral HPLC and by a stereospecific synthetic method. Binding assays have shown that the (S)-diastereomer is about fivefold more potent and selective than the (R)-diastereomer as agonist of the A2A receptor subtype [(S)-PHPNECA, KiA2A = 0.5 nM; (R)-PHPNECA, KiA2A = 2.6 nM]. Functional studies indicated that (S)-PHPNECA possesses marked vasodilating activity and produces a relevant decrease in heart rate. Moreover, the (S)-diastereomer proved to be about ten times more potent than the (R)-diastereomer in inducing cardiovascular effects, in in vivo hemodynamic studies. However, the greatest difference between these two enantiomers resulted in the platelet aggregation test: in fact, the (R)-diastereomer displayed an inhibitory activity similar to that of NECA, whereas the (S)-diastereomer was 37-fold more active than NECA as an inhibitor of rabbit platelet aggregation, induced by ADP. These data suggest that (S)-PHPNECA could be a useful tool to investigate the mode of binding of agonists to the platelet adenosine receptor subtype.
Camaioni
E
E
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Di Francesco
E
E
Vittori
S
S
Volpini
R
R
Cristalli
G
G
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
C111199:2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-5'-N-ethylcarboxamidoadenosine; D010975:Platelet Aggregation Inhibitors; D058906:Purinergic P1 Receptor Agonists; D000241:Adenosine